Clinical Review & Education Review Cellulitis A Review Adam B. Raff, MD, PhD; Daniela Kroshinsky, MD, MPH CME Quiz at IMPORTANCE Cellulitis is an infection of the deep dermis and subcutaneous tissue, presenting jamanetworkcme.com with expanding erythema, warmth, tenderness, and swelling. Cellulitis is a common global health burden, with more than 650 000 admissions per year in the United States alone. OBSERVATIONS In the United States, an estimated 14.5 million cases annually of cellulitis account for $3.7 billion in ambulatory care costs alone. The majority of cases of cellulitis are nonculturable and therefore the causative bacteria are unknown. In the 15% of cellulitis cases in which organisms are identified, most are due to β-hemolytic Streptococcus and Staphylococcus aureus. There are no effective diagnostic modalities, and many clinical conditions appear similar. Treatment of primary and recurrent cellulitis should initially cover Streptococcus and methicillin-sensitive S aureus, with expansion for methicillin-resistant S aureus (MRSA) in cases of cellulitis associated with specific risk factors, such as athletes, children, men who have sex with men, prisoners, military recruits, residents of long-term care facilities, those with prior MRSA exposure, and intravenous drug users. Five days of treatment is sufficient with extension if symptoms are not improved. Addressing predisposing factors can minimize risk of recurrence. CONCLUSIONS AND RELEVANCE The diagnosis of cellulitis is based primarily on history and Author Affiliations: Harvard Medical physical examination. Treatment of uncomplicated cellulitis should be directed against School, Massachusetts General Streptococcus and methicillin-sensitive S aureus. Failure to improve with appropriate first-line Hospital, Boston. antibiotics should prompt consideration for resistant organisms, secondary conditions that Corresponding Author: Daniela mimic cellulitis, or underlying complicating conditions such as immunosuppression, chronic Kroshinsky, MD, MPH, liver disease, or chronic kidney disease. 50 Staniford St, #200, Boston, MA 02114 ([email protected]). Section Editors: Edward Livingston, JAMA. 2016;316(3):325-337. doi:10.1001/jama.2016.8825 MD, Deputy Editor, and Mary McGrae McDermott, MD, Senior Editor. ellulitis is a bacterial infection of the skin, presenting with otic reference tools were also reviewed. Bibliographies of the poorly demarcated erythema, edema, warmth, and ten- retrieved studies and previous reviews were searched for other rel- C derness. Although common, it often can be a diagnostic and evant studies. Initially, 595 articles were identified for full review, therapeutic challenge. In this review, the pathophysiology, micro- and of these, the most pertinent 125 were selected for inclusion. biology, clinical presentation, and risk factors of cellulitis are dis- Articles were reviewed for the quality of evidence and contribution cussed. The approach to diagnosis is reviewed and the importance to current understanding of cellulitis, with priority given for clinical of differentiating cellulitis from clinical mimics of cellulitis is high- trials, large observational studies, and more recently published lighted. An approach to empirical treatment is presented, with re- articles. cent recommendations from the literature. Results Methods Epidemiology A literature search of the entire PubMed database was conducted The majority of epidemiology studies on cellulitis rely on Interna- with search terms and synonyms for cellulitis. The search was per- tional Classification of Diseases, Ninth Revision, codes (ie, 681.x and formed on October 9, 2014, and repeated on August 28, 2015. The 682.x) that unfortunately link cellulitis and abscess, creating some initial search identified 10 154 articles and the updated search iden- limitations. However, these data remain valuable by providing a gen- tified an additional 306. Studies published in non-English lan- eral scope of the problem and trends over time. guages (unless translated), and studies involving exclusively chil- Cellulitis or abscess is a common diagnosis whose incidence is dren or animals were excluded. Meta-analyses, systematic reviews, increasing and accounted for 10% of infectious disease–related US references cited in published clinical practice guidelines, and antibi- hospitalizations from 1998 to 2006,1 with annual US ambulatory jama.com (Reprinted) JAMA July 19, 2016 Volume 316, Number 3 325 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a University Of New Mexico User on 07/27/2016 Clinical Review & Education Review Diagnosis and Treatment of Cellulitis visits (outpatient and emergency departments) increasing from 4.6 burden, resulting in a greater likelihood that they would have sys- million in 1997 to 9.6 million in 2005.2 Furthermore, a significant temic signs of infection and undergo blood culture examination than proportion of patients with cellulitis are hospitalized for manage- the typical cellulitis patient. Because most cellulitis is treated em- ment, and inpatient numbers are increasing, with the number of pirically,bacterial pathogens are rarely identified in the disease, mak- hospital stays for cellulitis or abscess in the United States increasing ing it impossible to know the true frequency of bacterial etiologies. by 73%, from 12 per 10 000 in 1997 to 21 per 10 000 in 2011.3 In There has been increasing concern about antibiotic-resistant addition, a Netherlands study demonstrated that the total number bacteria, such as community-acquired methicillin-resistant S aureus of erysipelas, cellulitis, or abscess hospitalizations per inhabitants (MRSA), which is reflected in the increased use of anti-MRSA anti- per year increased markedly with age, with a 5-fold increase from biotics (eg, vancomycin, trimethoprim-sulfamethoxazole, doxycy- patients aged 54 years to those aged 85 years or older (incidence cline, clindamycin) and broad-spectrum gram-negative antibiotics >100 per 100 000).4 (eg, β-lactam/β-lactamase inhibitors, levofloxacin, ceftriaxone) during the past decade.40 However, most cases of cellulitis do not Pathophysiology involve gram-negative organisms, and in cases of nonpurulent Cellulitis is a deep dermal and subcutaneous infection that occurs and uncomplicated cellulitis, the addition of antibiotics against when pathogens gain entry into the dermis through breaks in the community-acquired MRSA did not improve outcomes.41 As such, skin. Cutaneous barrier disruption can be caused by toe web space narrow-spectrum antibiotics against Streptococcus and methicillin- bacteria, fungal foot infections (eg, tinea pedis, onychomycosis), sensitive S aureus remain appropriate. In purulent cellulitis (pres- pressure ulcers, and venous leg ulcers. Skin surface pathogenic or- ence of a pustule, abscess, or purulent drainage), S aureus infection ganism colonization is reduced by the presence of a low surface pH, is more likely, as demonstrated by a study of 422 patients who pre- low temperature, and commensal microorganisms. sented with “purulent skin and soft tissue infections” to 11 emer- The histologic features of cellulitis are nonspecific and include gency departments throughout the United States, in which dermal edema, lymphatic dilation, and diffuse, heavy neutrophil in- skin surface swab cultures revealed MRSA in 59% of patients, filtration around blood vessels. Later stages may also feature lym- methicillin-sensitive S aureus in 17%, and β-hemolytic streptococci phocytes and histiocytes, along with granulation tissue. in 2.6%.42 Because methicillin-sensitive S aureus and MRSA can be Usually, cultures performed with needle aspiration or biopsy difficult to differentiate according to clinical features alone,43 yield negative results, and when they are positive, the concentra- MRSA should be considered for purulent infections in known high- tion of bacteria is low.5,6 This suggests that either a very small num- risk populations, such as athletes, children, men who have sex with ber of bacteria are responsible for the induction of the robust in- men, prisoners, military recruits, residents of long-term care facili- flammatory response or the immune system reduces the number ties, individuals with previous MRSA exposure, and intravenous of viable bacteria to very low or nonexistent numbers by the time drug users.44 patients present for treatment. Bacterial toxins and other inflam- matory mediators that trigger an escalating inflammatory re- Clinical Presentation sponse may better define the pathogenesis of cellulitis than the bac- Cellulitis usually presents as an acute, spreading, poorly demar- terial load itself. cated area of erythema. The skin findings in cellulitis follow the clas- sic signs of inflammation: dolor (pain), calor (heat), rubor (erythema), Microbiology and tumor (swelling). Additional clinical features may include di- Cellulitis in immunocompetent adults is usually thought to be caused lated and edematous skin lymphatics, leading to a peau d’orange by group A streptococci (Streptococcus pyogenes), with Staphylo- (orange peel) appearance; bulla formation; or inflamed lymphatics coccus aureus as a notable but less common cause.7 However, given proximal to the area of cellulitis, leading to linear erythematous the difficulty culturing cellulitis, the specific causative bacterium in streaks or lymphangitis (Figure 1). Inflammation in the lymphatics most cases remains unknown, and several studies demonstrate